Abstract 1823: Imipridones show pre-clinical efficacy in <i>MYCN</i>-amplified and <i>MYCN</i> non-amplified neuroblastoma cell lines
Authors: Claire Lin, Wen-I Chang, Joshua N. Honeyman, Lanlan Zhou, Varun V. Prabhu, Joshua Allen, Wafik El-Deiry
Journal: Cancer Research (2022)

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 15% of all pediatric cancer-related deaths, with around 63% survival for high-risk patients. Treatment remains limited for advanced disease, calling for the development of novel therapies. We investigated the anti-tumor effect of three imipridones (ONC201, ONC206, and ONC212), a promising new class of small molecules, in the treatment of neuroblastoma. Imipridones are potent anticancer drugs that have previously shown efficacy for a variety of adult and pediatric malignancies. ONC201 and ONC206 are antagonists of dopamine receptor D2 (DRD2), while ONC212 is an agonist of GPR132, both of which are overexpressed in many cancers. We performed drug treatment with ONC201, ONC206, and ONC212 on established MYCN-amplified SK-N-BE(2) and MYCN non-amplified SH-SY5Y pediatric neuroblastoma cell lines in vitro. Cell viability assays were performed 72 hours post-treatment to generate dose responses curves. The IC50s for ONC201, ONC206, and ONC212 were 17.82 uM, 547 nM, and 70 nM for SK-N-BE(2), and 997 nM, 314 nM, and 6 nM for SH-SY5Y. Imipridones demonstrated greater efficacy for the non-MYCN-amplified cell line. Using protein quantification studies and downstream target analysis on drug-treated cells, we investigated the mechanisms of how these therapies caused cell death. We showed that imipridones inactivate cell proliferation kinases Akt/ERK and induce cell death through the pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). They also induce tumor cell apoptosis by modifying the mitochondrial Clp protease complex, decreasing expression of chaperone subunit ClpX and activating mitochondrial proteolysis. Histone deacetylases (HDACs) play a role in controlling MYCN function, which is amplified in more aggressive neuroblastoma; HDAC activity and MYCN are also upregulated in chemotherapy-resistant neuroblastoma. Cell viability assays with HDAC inhibitors Vorinostat and Panobinostat demonstrated single-agent efficacy in vitro. The IC50s for Vorinostat and Panobinostat were 609 nM and 5.51 nM for SK-N-BE(2), and 884 nM and 6.13 nM for SH-SY5Y. However, further investigation is needed to determine synergy and mechanisms of synergy when histone deacetylase (HDAC) inhibitors are used in novel combinations with imipridones. Overall, our data reveals promise in imipridone therapy for neuroblastoma, and future studies are proposed to explore potential novel therapeutic combinations in this difficult-to-treat pediatric cancer. Citation Format: Claire Lin, Wen-I Chang, Joshua N. Honeyman, Lanlan Zhou, Varun V. Prabhu, Joshua Allen, Wafik El-Deiry. Imipridones show pre-clinical efficacy in MYCN-amplified and MYCN non-amplified neuroblastoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1823.